Methods And Pharmaceutical Preparations For Normalizing Blood Pressure With (xe2x88x92)-Hydroxycitric Acid
1. Field of the Invention
This invention relates to pharmaceutical compositions containing (xe2x88x92)-hydroxycitric acid useful for correcting Polymorphic Metabolic Dysfunction (PMD) in individuals in need thereof by influencing the metabolism of insulin, glucocorticoids and leptin and the relationship of these to the resistin-peroxisome proliferator-activated receptor xcex3 (PPARxcex3) axis.
2. Description of Prior Art
According to the National Heart, Lung, and Blood Institute (1999), an estimated 97 million adults in the United States are overweight or obese, conditions which substantially raise their risks of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems, and endometrial, breast, prostate, and colon cancers. The percentage of overweight and obese men and women as a fraction of the populace at large has risen dramatically since 1960; in 1999, the estimated percentage of people in these categories has increased to approximately 55 percent of adults aged 20 years or older. The World Health Organization and the National Heart, Lung and Blood Institute of the National Institutes of Health have classified obesity as an epidemic inasmuch as the incidence of obesity in children and adults has increased by nearly 50% in the past decade. Significantly, it is increasingly recognized that unwanted weight often is indicative of intractable metabolic changes which are poorly treated over the long term with simple anorectic agents and which are substantially aggravated by bouts of dieting. As this suggests, the traditional focus upon weight loss and the treatment of obesity per se very commonly has been and remains nonproductive.
Leptin is the best known of the primary signals for the communication of body fat information to the central nervous system. Identification of this peptide in 1994 provided major new insights into the regulation of food intake, energy expenditure and body fat maintenance. It is now clear that this compound, which is derived primarily from fat cells, reduces food intake and increases the activity of the thermogenic components of the sympathetic nervous system in metabolically normal individuals.
Leptin production is stimulated by insulin and glucocorticoids, but inhibited by beta-adrenergic stimulation. Circulating levels of leptin are correlated with the level of body fat. The peptide exerts its effects through leptin receptors in the central nervous system. Modulation of neurons by leptin results in a reduction in the secretion of neuropeptide Y (NPY), a reduction in the secretion agouti-related protein (AGRP), and an increase in the secretion of proopiomelanocortin (POMC), the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which reduces food intake. When researchers have examined the role of leptin in weight loss, injections in lean and obese subjects have had a dose-related effect upon weight and fat loss. However, there was significant discomfort at the injection site. For leptin to be clinically acceptable, the route of delivery must be improved. Alternatively, a solution would include indirect methods of influencing leptin secretion and/or sensitivity.
The use of a leptin-controlling alternative is all the more crucial because although injected leptin has shown some promise in reducing unwanted weight, its effects are not well understood and may be negative. A surprising and disappointing finding in one study was that some 30 percent of all the leptin-treated subjects actually gained weight during this trial, in comparison with one half of the placebo subjects. Moreover, inasmuch as leptin levels in the obese are already highxe2x80x94the obese may have three to five times as much leptin in their blood as do normal weight individuals, but only 20 percent more leptin in their brainsxe2x80x94overcoming leptin resistance via exogenous leptin may require the continuous use of quite large amounts of the compound and bring its own array of side effects. As is the case of with insulin, which is taken by diabetics to overcome insulin resistance, excessive levels of leptin may not be innocuous. Indeed, studies have shown a strong correlation between elevated leptin levels and the insulin resistance syndrome. A causal model for leptin""s role in insulin resistance has been offered by several teams of researchers. (Girard J. Is leptin the link between obesity and insulin resistance? Diabetes Metab. September 1997;23 Suppl 3:16-24; Spiegelman B M, Flier J S. Adipogenesis and obesity: rounding out the big picture. Cell. Nov. 1, 1996;87(3):377-89; Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science. Nov. 15, 1996;274(5290): 1185-8.) Conversely, it might be argued that the initial issue is that of insulin resistance itself and that this metabolic syndrome or Syndrome X blunts the normal physiologic effects of leptin. (Boden G, Chen X, Kolaczynski J W, Polansky M. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest. Sep. 1, 1997;100(5):1107-13.)
Adrenal glucocorticoids, such as cortisol and corticosterone, play an important role in the neuroendocrine control of food intake and energy expenditure. Experimental evidence demonstrates that glucocorticoids are critical for the development and maintenance of obesity, that is, obesity is linked to increases in glucocorticoid production and/or to hyperresponsiveness to glucocorticoids in the hypothalaniic-pituitary-adrenal axis. Glucocorticoids have been shown to be necessary if the chronic intracerebroventricular infusion of neuropeptide Y is to produce obesity and related abnormalities. Obversely, adrenalectomy in animals with a lesion to the ventromedial hypothalamus will reverse obesity. In humans, excess production of glucocorticoids produces modest obesity, and destruction of the adrenal glands is associated with a loss of body fat. Significantly, it has been found that glucocorticoids inhibit the body weight-lowering effect of leptin. (Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. Diabetes April 1997;46(4):7 17-9.)
Both neuropeptide Y and leptin act within the hypothalamus, yet the effects of the glucocorticoids in promoting weight gain may be realized peripherally as well as centrally. In an animal experiment, a continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion, which was sufficient to abolish endogenous corticosterone output, produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities typical of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and a decrease in the expression of UCP-3 in muscle, i.e., infusion resulted in a marked decrease in the expression of the xe2x80x9cthermogenicxe2x80x9d proteins. Chronic central glucocorticoid administration increased hypothalamic levels of neuropeptide Y. (Zakrzewska K E, Cusin I, Stricker-Krongrad A, Boss 0, Ricquier D, Jeanrenaud B, Rohner-Jeanrenaud F. Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. Diabetes February 1999;48(2):365-70.) Through perhaps unrelated means, glucocorticoids induce insulin resistance. (Weinstein SP, Paquin T, Pritsker A, Haber R S. Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli. Diabetes. April 1995;44(4):441-5.)
Closely related to the physiologic actions of insulin and leptin are the linked actions of resistin and peroxisome proliferator-activated receptor xcex3 (PPARxcex3). Only very recently, a team of researchers demonstrated that adipocytes secrete a unique signaling molecule which they named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone and other thiazolidinedione (TZD) drugs, but increased in diet-induced and genetic forms of obesity. Administration of an anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Conversely, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes. There is a very notable overlap in the physiologic functions controlled by resistin and those controlled by PPARxcex3. Moreover, as is shown by the efficacy of the TZD drugs, which target PPARxcex3 and also reduce resistin levels, the cellular regulatory mechanisms governing resistin and PPARxcex3 appear to be linked. (Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes. Nature. Jan. 18, 2001;409(6818):307-12; Kee-Hong Kim, Kichoon Lee, Yang Soo Moon, and Hei Sook Sul. A Cysteine-rich Adipose Tissue-specific Secretory Factor Inhibits Adipocyte Differentiation. The Journal of Biological Chemistry Apr. 6, 2001;276(14):11252-11256.) From another angle, new research is increasingly showing that the transcription of the insulin receptor gene promoter is controlled by the same regulatory sequences which govern leptin, fatty acid synthase and other glucose/insulin responsive cellular elements. (Fukuda H, Noguchi T, Iritani N. Transcriptional regulation of insulin receptor gene promoter in rat hepatocytes. Biochem Biophys Res Commun. Feb. 9, 2001;280(5):1274-8.)
Unclear in this picture is whether the core syndrome is insulin resistance, sometimes termed Syndrome X or the xe2x80x9cmetabolicxe2x80x9d syndrome, or whether at work are overlapping and causally-related mechanisms. In recognition of the fact that (1) elevated insulin levels can lead to elevated leptin levels, which in turn will promote insulin resistance; (2) elevated leptin levels and subsequent leptin resistance may prove in some cases to be the initial alteration which induces insulin resistance; (3) sustained elevations in the glucocorticoids may promote either or both insulin and/or leptin resistance through the mechanisms outlined and yet others; and (4) resistin and/or the resistin-PPARxcex3 axis, similarly, is tied to insulin resistance, leptin levels, etc., the authors propose to view excessive weight gain as often being indicative of a Polymorphic Metabolic Dysfunction (PMD) in which these factors are linked.
Unrelated to these recent developments in obesity research according to published literature are the actions of (xe2x88x92)-hydroxycitric acid. (xe2x88x92)-Hydroxycitric acid (abbreviated herein as HCA), a naturally-ocurring substance found chiefly in fruits of the species of Garcinia, and several synthetic derivatives of citric acid have been investigated extensively in regard to their ability to inhibit the production of fatty acids from carbohydrates, to suppress appetite, and to inhibit weight gain. (Sullivan AC, Triscari J. Metabolic regulation as a control for lipid disorders. I. Influence of (xe2x88x92)-hydroxycitrrate on experimentally induced obesity in the rodent. American Journal of Clinical Nutrition 1977;30:767.)
Weight loss benefits were first ascribed to HCA, its salts and its lactone in U.S. Pat. No. 3,764,692 granted to John M. Lowenstein in 1973. The claimed mechanisms of action for HCA, most of which were originally put forth by researchers at the pharmaceutical firm of Hoffimann-La Roche, have been summarized in at least two United States Patents. In U.S. Pat. No. 5,626,849 these mechanisms are given as follows: xe2x80x9c(xe2x88x92) HCA reduces the conversion of carbohydrate calories into fats. It does this by inhibiting the actions of ATP-citrate lyase, the enzyme which converts citrate into fatty acids and cholesterol in the primary pathway of fat synthesis in the body. The actions of (xe2x88x92) HCA increase the production and storage of glycogen (which is found in the liver, small intestine and muscles of mammals) while reducing both appetite and weight gain. (xe2x88x92) Hydroxycitric acid also causes calories to be burned in an energy cycle similar to thermogenesis . . . (xe2x88x92) HCA also increases the clearance of LDL cholesterol . . . . xe2x80x9d U.S. Pat. No. 5,783,603 further argues that HCA serves to disinhibit the metabolic breakdown and oxidation of stored fat for fuel via its effects upon the compound malonyl CoA and that gluconeogenesis takes place as a result of this action. The position that HCA acts to unleash fatty acid oxidation by negating the effects of malonyl CoA with gluconeogenesis as a consequence (McCarty MF. Promotion of hepatic lipid oxidation and gluconeogenesis as a strategy for appetite control. Medical Hypotheses 1994;42:215-225) is maintained in U.S. Pat. No. 5,914,326.
HCA has not been suggested in any published literature as a compound with the ability to lower blood sugar levels, to improve glucose metabolism, to lower insulin levels, to influence glucocorticoid levels, to alter leptin levels or to have any influence upon resistin or PPARxcex3. Indeed, the precise mechanisms of action of the drug remain largely unexplained. For instance, the original pharmaceutical research on HCA performed at Hoffman-La Roche failed to find significant changes in either blood glucose levels or blood insulin levels, undoubtedly in large part due to the fact that almost all of that research used diets which consisted preponderantly of glucose as the source of calories (e.g., 70% glucose diets were typically employed to encourage lipogenesis). Such a diet might easily mask the effects of a compound which amplified the body""s normal physiologic mechanisms of glucose control rather than substituting for these or even blocking normal pathways. The conclusion of the Roche researchers was that xe2x80x9cno significant differences in plasma levels of glucose, insulin, or free fatty acids were detected in (xe2x88x92)-hydroxycitrate-treated rats relative to controls. These data suggest that peripheral metabolism, defined in the present context as metabolite flux, may be involved in appetite regulation . . . xe2x80x9d (Sullivan, Ann C. and Joseph Triscari. Possible interrelationhip between metabolite flux and appetite. In D. Novin, W. Wyriwicka and G. Bray, eds., Hunger: Basic Mechanisms and Clinical Implications (New York: Raven Press,1976) 115-125.) No Roche data was ever published linking HCA to changes in glucocorticoid levels; leptin, resistin and PPARxcex3 had not even been discovered at the time of the Roche HCA trials.
Some early preliminary work showed that labeled 14C attached to HCA found its way into the brain. (Sullivan A C, Triscari J. Metabolic regulation as a control for lipid disorders. I. Influence of (xe2x88x92)-hydroxycitrrate on experimentally induced obesity in the rodent. American Journal of Clinical Nutrition 1977;30:767.) However, work published by the same authors at a later date indicated otherwise. xe2x80x9cHydroxycitrate, chlorocitrate, and epoxyaconitate, compounds that are structurally similar to the tricarboxylic acid cycle intermediate citric acid, but that differ markedly in biochemical activity, have recently been evaluated in animals for effects on appetite. Because neither these compounds nor their metabolites enter the brain, their primary effects on food intake occur by peripheral mechanisms.xe2x80x9d (Sullivan A C, Gruen R K. Mechanisms of appetite modulation by drugs. Federation Proceedings 1985;44,1:139-144.)
Despite the published conclusions by the Roche researchers, the present inventors have discovered that HCA, in fact, does reduce glucocorticoid, insulin and leptin levels in animals which are fed a diet in which the calories are not derived predominantly from simple sugars. The inventors, moreover, have found that these reductions act independently of HCA""s established appetite-suppressing effect to lead to a lasting reduction in the tendency to gain weight even when food intake increases to the level of that eaten by controls. Whether this benefit is a result of a disinhibited expression of uncoupling proteins (UCP-1 and UCP-3, primarily) or is a result of a less direct effect upon leptin, PPARxcex3 and/or insulin sensitivity has not been conclusively established. The present authors consider the effect as arising from the correction of one or more arms of the Polymorphic Metabolic Syndrome (PMD) described above.
Of the readily available forms of HCA, only the potassium and sodium salts of HCA are absorbed well enough to be effective agents at tolerable levels of ingestion. Reasons for this are given in the inventors"" copending U.S. Patent Application xe2x80x9cPotassium (xe2x88x92)-Hydroxycitric Acid Methods For Pharmaceutical Preparations For Stable And Controlled Delivery.xe2x80x9d Derivatives of HCA may also be active and effective in this regard. (U.S. Pat. Nos. 3,993,668; 3,919,254; 3,767,678.) Liquid forms of HCA currently in use are irritating to the digestive system, depending upon the dose, and may cause an elevation of stress hormones as a result. Researchers have found that animals given high doses of the liquid form of the compound orally exhibit stress behavior. (Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (xe2x88x92)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. December 2000;130(12):2990-5.) Similarly, the ethylenediamine salts of HCA used in some of the later research performed by Hoffman-La Roche are known to be irritating and even toxic, properties which are due to the ethylenediamine ligand and not to the HCA. In contrast to the quite limited efficacy found with the calcium salt and some other delivery forms of HCA, the impact of ingestion of appropriate amounts of the appropriate salts of HCA upon corticosterone levels has been positive, as has the impact upon insulin and leptin levels in diets which calorically are not predominantly composed of sugars.
This picture is complicated considerably by the fact that all of the more recent and more thorough clinical trials on HCA not only have failed to produce appetite suppression, but alsoxe2x80x94and surprisingly in light of the claims made in several HCA patents already grantedxe2x80x94have produced trends toward weight gain. (Heymsfield S B, Allison D B, Vasselli J R, Pietrobelli A, Greenfield D, Nunez C. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial. JAMA. 1998;280:1596-1600; also Mattes R D, Bormann L. Effects of(xe2x88x92)-hydroxycitric acid on appetitive variables. Physiol Behav. Oct. 1, 2000;71(1-2):87-94.) Although they did not pursue the matter thoroughly, two Roche researchers in 1977 showed that HCA in the cytosol of the cell will activate acetyl CoA carboxylase similarly to the citrate it resembles. The effect of this property is that in diets which supply a source of acetyl CoA to the cytosol other than via citrate derived from the mitochondria, which means diets containing appreciable amounts of fat or alcohol as opposed to diets consisting almost exclusively of carbohydrates, HCA may increase the synthesis of fats and weight gain. (Triscari J, Sullivan A C. Comparative effects of (xe2x88x92)-hydroxycitrate and (+)-allo-hydroxycitrate on acetyl CoA carboxylase and fatty acid and cholesterol synthesis in vivo. Lipids April 1977;12(4): 357-363.)
Not a single one of the patents which have been granted to date for the employment of HCA as an antiobesity agent (U.S. Pat. Nos. 3,764,692; 5,626,849; 5,783,603; 5,914,326 and others proposing the use of HCA as an adjunctive ingredient) has indicated any awareness of this paradoxical effect, an effect which has led to either null or negative results in the major clinical trials with HCA up to the point of this writing. Two very recently granted HCA patents are no more enlightening on the paradoxical qualities of HCA. In U.S. Pat. No. 6,217,898 which tested calcium hydroxycitrate either alone or in combination with L-carnitine, the diet used consisted of 50% glucose and only 1% calories from fat in animals given calcium hydroxycitrate (CaHCA) as 1-2% of their total food intake. The human equivalent would be at least 10-20 grams intake of CaHCA per day on a diet which is pharmaceutically fat free. In fact, CaHCA is very poorly absorbed, and the published research literature found in peer-reviewed journals as already discussed would seem to indicate that the test results given in U.S. Pat. No. 6,217,898 will not be reproducible outside of the narrow diet employed. No mention is made in this patent of the variables given above as aspects of PMD, i.e., insulin, leptin, glucocorticoids, resistin or PPARxcex3.
Similarly, U.S. Pat. No. 6,221,901 teaches a method for the production of magnesium (xe2x88x92)-hydroxycitrate and makes claims for the benefits of magnesium when (xe2x88x92)-hydroxycitric acid is employed as the ligand in conjunction with at least one indicated vitamin or additional metal. The experimental dosages used to generate the animal data were extraordinarily high (500 mg MgHCA/kg body weight/day in the rats and 750 mg/kg body weight/day in rabbits). In the in vivo animal experiments, there were no separate non-HCA magnesium arms and therefore no proof that any other good source of magnesium would not have yielded statistically similar results. Further, the authors of U.S. Pat. No. 6,221,901 give no evidence that the very low dosage of MgHCA listed in the claimsxe2x80x94starting at 50 mg MgHCA per dayxe2x80x94will provide any benefits to humans inasmuch as even the individual rats in the tests cited were being dosed at roughly 125 mg MgHCA/day, i.e. rats weighing roughly 0.3 kg were tested with a total daily dose of MgHCA more than twice that claimed to be efficacious in a 70 kg human. Likewise, the 3 kg rabbits received approximately 250 mg MgHCA each day, yet the test results are extrapolated to a 70 kg human ingesting only 50 mg MgHCA per day. No mention is made in the patent of aspects of PMD, i.e., no mention is made of issues involving the metabolism of insulin, leptin, glucocorticoids, resistin or PPARxcex3.
Animal trials conducted by the present inventors have confirmed the danger of the weight gain effect of HCA when the compound is delivered at an inadequate dosage level or in an inappropriate manner of intake, especially in conjunction with a diet containing nontrivial amounts of fats. Certainly, the typical American dietary pattern in which calories derived from fats account for at least 30% of the total caloric intake is sufficient to cause supplementation with HCA to upregulate acetyl CoA carboxylase and, subsequently, the synthesis of fatty acids from acetyl CoA.
In discovering the ability of HCA to correct Polymorphic Metabolic Dysfimction, the present authors have uncovered that HCA exhibits a twofold biphasic nature. First, the weight loss effects found with HCA during the first several weeks of use appear to be dependent primarily upon anorexia caused by a delay in gastric emptying. The suggestion by Roche researchers that the appetite suppression found with the compound is dependent upon glucoreceptors in the liver has never been fully reconciled with the rapid onset of satiety caused by HCA once a meal was begun as long as the compound was already in the system. However, action upon receptors in the small intestine and delay in gastric emptying does explain the observed effects of the compound quite handily. Moreover, although Roche never published data on HCA and gastric emptying in journal articles or in other scientific forums, the company did obliquely reveal that HCA works by delaying stomach emptying in its patents on chlorocitric acids (e.g., U.S. Pat. No. 4,443,619.) Moreover, various documents detailing Roche animal experiments found in the public domain show that the appetite-controlling aspects of HCA decline after several weeks of ingestion of the compound, and the present authors can support this with their own animal findings, which indicate a steep drop-off in anorectic effect which becomes significant sometime after about six weeks of use. The effects of HCA upon Polymorphic Metabolic Dysfunction remain, however, after the effects upon appetite have disappeared.
Second, HCA is biphasic in at least one other sense, and that is in its differential outcome depending upon whether it is supplied at an adequate level and/or in an appropriate manner of delivery. The present authors"" animal experiments have confirmed that some HCA salts sold commercially and utilized for failed clinical trials will cause weight gain in animals under experimental conditions in which fats account for 30% of ingested calories. These commercial salts appear to suffer from poor assimilation and/or there is some problem with the nature of the compound which is delivered into the body inasmuch as even the so-called solubilized salts which are mixtures of potassium and calcium fail to reduce weight gain in animal experiments. In contradistinction to these commercial HCA products, the same amount of HCA delivered from a fairly good quality potassium salt under the same conditions as indicated above and discussed below under Preferred Embodiments inhibited weight gain in this animal experiment. Furthermore, in at least one animal experiment, the use of a patented admixture (as described in U.S. Pat. No. 5,626,849 and produced according to the examples given there) which employed a poor quality HCA salt yielded weight loss benefits which were not better than those found with the salt alone or with placebo. Hence, under most circumstances, the quality of the source of HCA is likely to be more significant than will be any auxiliary compounds claimed to augment the efficacy of the HCA.
No prior art suggests that HCA can be used to counteract elevated glucocorticoid levels, hyperinsulinemia or hyperliptinemia, nor that HCA can affect resistin or peroxisome proliferator-activated receptor xcex3. No prior art teaches that HCA can counteract unwanted effects of elevated levels of these hormones and thus normalize metabolic functions. The present inventors therefore have discovered a novel means of correcting the Polymorphic Metabolic Dysfunction.
The inventors have discovered that HCA is useful in reducing or even correcting Polymorphic Metabolic Dysfunction (PMD), here defined as a syndrome in which there resistance to the actions of insulin and/or leptin, usually both, with a pathological involvement of the glucocorticoids and dysregulation of resistin and/or peroxisome proliferator-activated receptor xcex3 (PPARxcex3). This action by HCA with regard to PMD has not heretofore been recognized. The benefits of HCA in reducing polymorphic metabolic dysfunction are especially pronounced with the use of the preferred salt of the acid, potassium hydroxycitrate, and may be further potentiated by the use of a controlled-release form of the compound. The discovery that HCA has Polymorphic Metabolic Dysfunction-moderating effects allows for the creation of novel and more efficacious approaches to preventing obesity, for maintaining normal metabolic functioning even in the face of diet and exercise habits which are less than ideal, for preventing the development of insulin resistance and its attendant well-documented health risks, and for preventing or moderating the damaging effects which are associated with elevated levels of circulating insulin, leptin, glucocorticosteroids, resistin and/or dysfunctions involving peroxisome proliferator-activated receptor xcex3. Furthermore, this discovery makes possible the development of adjuvant modalities which can be used to improve the results realized, for instance, from treatment with leptin and other xe2x80x9cweight lossxe2x80x9d compounds while at the same time reducing the side effects normally found with such drugs. HCA delivered in the form of its potassium salt is efficacious at a daily dosage (bid or tid) of between 750 mg and 10 grams, preferably at a dosage of between 3 and 6 grams for most individuals. A daily dosage above 10 grams might prove desirable under some circumstances, such as with grossly obese or resistant individuals, but this level of intake is not deemed necessary under normal conditions.
It is an objective of the present invention to provide a method for treating or ameliorating Polymorphic Metabolic Dysfunction. It is a further object of the present invention to provide a means of treating or ameliorating Polymorphic Metabolic Dysfunction by addressing the primary elements of this disorder: elevated insulin, leptin and stress hormone levels as well as dysregulation of resistin and/or peroxisome proliferator-activated receptor xcex3. These elevations and dysfunctions are usually accompanied by resistance to the actions of insulin and leptin. It is yet a further advantage of the present invention to provide a meansxe2x80x94one which is accompanied by few or no side effectsxe2x80x94of maintaining proper metabolic functioning and energy expenditure as well as stabilizing weight without resort to caloric restriction or special diets. Knowledge of the present invention has the advantage of allowing the use of forms of (xe2x88x92)-hydroxycitric acid, including especially through controlled release formulations, as adjuvants to obesity drugs and to drugs designed to stabilize or improve long term energy balance. These objects and advantages are not derived from the anorectic actions commonly claimed for the use of HCA as an anti-obesity agentxe2x80x94actions which animal trials indicate may not last longer than roughly six or seven weeks, in any eventxe2x80x94but rather are found with the extended use of the compound and rely upon mechanisms not heretofore uncovered.